The principle objective of this project is to define and characterize the consequences of HIV-1 envelope mediated signals on CD4+ T-cells and macrophages. We are specifically interested in how envelope-receptor interactions influence viral replication and HIV associated immune system dysfunction. Immunopathogenic events that occur during the course of HIV infection may be mediated directly by interactions between virions and target cells, as well as indirectly by interactions between virion components (i.e., HIV envelope glycoproteins) and cells. We have established systems that allow us to investigate HIV-1 envelope mediated signal transduction of CD4+ lymphocytes and macrophages in vitro. In order to characterize the response of lymphocytes and macrophage to HIV envelopes we have expressed and purified recombinant forms of macrophage tropic and T-cell tropic HIV-1 and SIV envelope proteins. We have demonstrated that HIV envelope proteins interact directly with the HIV-1 coreceptor CCR5 in addition to the CD4 receptor. We have further demonstrated that this interaction results in signal transduction as measured by calcium mobilization. These responses occur in both CD4+ T-lymphocytes and macrophages. Furthermore these responses are dependent upon the coreceptor specificity of the envelope employed.We have further addressed the role of HIV envelope proteins by characterizing intracellular signalling events associated with envelope-receptor interaction. To this end we have demonstrated that HIV envelope induces caspase-3 and 6 in primary peripheral blood monoclear cells (PBMCs). Both R5 and X4 envelopes carry out this function. In addition we found that envelope induced the cleavage of phosphorylated focal adhesion kinase (FAK). Regarding the role of envelope signal transduction in viral replication we demonstrated that envelopes derived from macrophage tropic isolates of HIV and SIV induce calcium mobilization in monocyte-derived-macrophages while non-macrophage tropic viruses do not, or do so inefficiently.